Interstitial lung diseases are characterized by inflammation and fibrosis that can be caused by toxic agents such as dusts, particles, drugs, or infectious agents. Regardless of the initiating agent, pulmonary fibrosis induced by inhaled toxicants shares common features, which include inflammation, proliferation of interstitial cells, and deposition of extracellular matrix. We have been studying the molecular mechanisms of pulmonary fibrosis induced by asbestos, a model fibrogenic agent. Such materials upregulate a variety of genes in lung, but the genes that are the key, initiating mediators of pulmonary fibrosis have not been identified. We have studied platelet-derived growth factor (PDGF) as a candidate mediator of pulmonary fibrosis. PDGF is the most potent mesenchymal cell mitogen known, and has also been implicated as an inducer of extracellular matrix secretion. We have found that the levels of PDGF in the lungs of laboratory rodents increase dramatically after inhalation of a fibrogenic dose of chrysotile asbestos. A particularly high level of asbestos-induced PDGF expression is found in epithelial cells. We propose a model in which the fibroproliferative response caused by inhalation of a fibrogenic agent is driven by PDGF released from the overlying epithelial cells. The central hypothesis to be tested here is that epithelial-derived PDGF is a key mediator of interstitial pulmonary fibrosis. The hypothesis will be tested in transgenic mice that overexpress PDGF subunit genes or a dominant-negative PDGF mutant from the lung epithelial-specific surfactant protein C (SPC) gene promoter. The SPC promoter will be used to overexpress genes encoding the PDGF A and PDGF B genes singly and in combination to assess the potential of PDGF isoforms to initiate pulmonary fibrosis in the absence of a fibrogenic agent. These transgenic mice will be exposed to asbestos to examine the combined effect of PDGF overexpression and asbestos-induced lung injury. Transgenic mice will also be generated that express a dominant-negative form of PDGF to determine whether interference with epithelial-derived PDGF function prevents asbestos-induced lung injury. The proposed experiments will allow a determination of which features of pulmonary fibrosis can be initiated by PDGF and which require other triggering events. Identification of PDGF as a key mediator of fibrosis would serve to establish this factor as a target for therapeutic intervention in interstitial lung disease.